The compound 1-(N2-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl)-L-proline, having the generic name lisinopril, as well as therapeutically acceptable salts thereof, are described in U.S. Pat. Ser. No. 4,374,829 (Merck and Co. Inc.), incorporated herein by reference. In said patent the compound is described in Example 119, and is referred to as N-xcex1-[1 (S)-1-carboxy-3-phenylpropyl]-L-lysyl-L-proline. The divisional application of the ""829 patent, which has resulted in U.S. Pat. No. 4,472,380, incorporated herein by reference, claims pharmaceutical compositions that include lisinopril pharmaceutical compositions. Lisinopril is a drug on which extensive clinical experience has been obtained. It is currently sold in the United States under the trademark ZESTRIL(copyright) by AstraZeneca or PRINIVIL(copyright) by Merck and Co. A combination of lisinopril and hydrochlorothiazide is sold under the trademarks ZESTORETIC(copyright) by AstraZeneca or PRINZIDE(copyright) by Merck and Co. ZESTRIL(copyright) and ZESTORETIC(copyright) are manufactured by wet granulation tabletting using milled DCPD.
A typical lisinopril formulation consists of lisinopril dihydrate, which can be any dose from 1mg-100 mg, the fillers (diluents)-dibasic calcium phosphate dihydrate and mannitol, maize starch as a binder and disintegrant and magnesium stearate as a lubricant.
Lisinopril is a peptidyl dipeptidase inhibitor useful in treating cardiovascular diseases and disorders, such as hypertension and congestive heart failure (CHF) in mammals and especially in man. It inhibits the angiotensin converting enzyme (ACE) that catalyses the conversion of angiotensin I to the vasoconstrictor peptide, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased concentrations of angiotensin II which results in decreased vasopressor activity and reduced aldosterone secretion.
ACE is known to be present in the endothelium and increased ACE activity in diabetic patients which results in the formation of angiotensin II and destruction of bradykinin, potentiates the damage to the endothelium caused by hyperglycaemia. ACE inhibitors, including lisinopril, inhibit the formation of angiotensin II and breakdown of bradykinin and hence ameliorate endothelial dysfunction.
Dibasic calcium phosphate dihydrate (DCPD, CaHPO4.2H2O) is a diluent used in tablet and capsule formulations. It is used both as an excipient (diluent/filler) and as a source of calcium in nutritional supplements. It is used in pharmaceutical products because of its compaction properties, and the good-flow properties, particularly the coarse-grade material. Two main particle-size grades of DCPD are used in the pharmaceutical industry, milled and unmilled. The former material is typically used in wet-granulated or roller-compacted formulations whereas the latter coarse-grade material is typically used in dry, direct-compression formulations.
Synonyms and trademarks for dibasic calcium phosphate dihydrate are: Cafos; calcium hydrogen orthophosphate dihydrate; calcium monohydrogen phosphate dihydrate; Calstar; Calipharm; dicalcium orthophosphate; Difos; DI-TAB; E341; Emcompress; phosphoric acid calcium salt (1:1) dihydrate; secondary calcium phosphate; calcium phosphate; and dicalcium phosphate, the latter two terms are commonly used generic terms in the pharmaceutical art.
Dibasic calcium phosphate dihydrate is white, odourless, tasteless, nonhygroscopic and stable at room temperature. However, under certain conditions of temperature and humidity, it can lose water of crystallization below 100xc2x0 C.
On long-term storage, when in the formulated product and particularly with low dosage formulations, lisinopril has a tendency to form diketopiperazine (DKP), a lisinopril degradation product or metabolite, which limits the shelf life for low dose formulations. The inventors have found a correlation between the amount and speed of DKP formation and the particle size of the co-formulated dibasic calcium phosphate dihydrate excipient.
It has previously been disclosed that when formulated as a tablet with large particle sizes of DCPD, aspirin has a reduced propensity to degrade to salicylic acid and acetic acid compared to aspirin formulated as a tablet with smaller particle sized DCPD (Landin et al., (1994) Int. J. Pharm. 107:247-249; Landin et al., (1995) Int. J. Pharm. 123:143-144). The mechanism for the degradation of aspirin to salicylic acid and acetic acid is hydrolysis (Leesen and Mattocks (1958) J. Am. Pharm. Sci. Ed., 67:329-333.). DCPD, which is known to readily dehydrate, provides water to promote the process. The poorer stability of tablets containing powdered material of DCPD as compared to aggregated material was attributed to a greater propensity of smaller particle size DCPD to lose more water (Landin et al., 1994, 1995, supra).
The breakdown of lisinopril to form DKP is, however, not a hydrolysis (the addition of water) but dehydration (loss of water) within the lisinopril molecule. Because the mechanism of action involved with aspirin and lisinopril degradation are completely different, it would not have been predictable that use of larger particle sized DCPD would also reduce the amount of lisinopril degradation.
The present invention relates to a composition comprising 1-(N2-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl)-L-proline and processes for making the composition. 1-(N2-[(S)-1-carboxy-3-phenylpropyl]-L-lysyl)-L-proline is known under the generic name lisinopril. The novel composition is made with dibasic calcium phosphate dihydrate (DCPD, CaHPO4.2H2O) that possesses a low specific surface area of less than 1.5 m2gxe2x88x921 as determined by nitrogen adsorption (BET method). The use of large-particle DCPD in a lisinopril formulation/composition has the effect of reducing the amount of the lisinopril degradation product diketopiperazine (DKP) that is formed, which would increase the shelf-life of tablets formulated with the large-particle DCPD, particularly those containing low dosage amounts of lisinopril.
It has surprisingly been found that the lisinopril tablets formulated with large particle sized DCPD (unmilled) have a reduced tendency to form the lisinopril degradation product, diketopiperazine (DKP), particularly in low dosage lisinopril tablets. It is an object of the present invention to provide lisinopril tablets that have been made with larger particle sized DCPD than currently used, with the intention of reducing the amount of DKP degradation product that forms.
The invention is not limited by the tabletting method. The large particle DCPD can be used to form lisinopril tablets by either the previously employed wet-granulated method or by a dry, direct-compression method, of the same type, familiar to those skilled in the art, that is used for other products. The amount of large particle DCPD can be as low as 30% (w/w) of the tablet to obtain the benefit of the invention.
Thus, according to a first aspect of the invention there is provided a solid pharmaceutical composition comprising lisinopril, and an excipient, which comprises DCPD with a specific surface area of less than 1.5 m2gxe2x88x921 prior to compaction or tabletting in an amount that is at least 30% (w/w) of the composition.
According to a further aspect of the invention there is provided a tablet, produced by either wet granulation tabletting or dry direct-compression tabletting comprising lisinopril, and an excipient, comprising lisinopril and an excipient which comprises DCPD with a specific surface area of less than 1.5 m2gxe2x88x921 prior to tabletting in an amount that is at least 30% (w/w) of the composition.
According to a further aspect there is provided a tablet comprising lisinopril, an excipient comprising mannitol and DCPD, magnesium stearate, and maize starch.
According to a further aspect of the invention there is provided a pharmaceutical composition in tablet form containing an amount of lisinopril selected from 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg and 40 mg wherein the amount of lisinopril is expressed as the weight of anhydrous lisinopril (e.g. 30 mg Zestril tablets contain 32.67 mg of lisinopril dihydrate).
In a preferred embodiment of each of the aspects of the present invention, the dibasic calcium phosphate dihydrate has a specific surface area of less than 1.5 m2gxe2x88x921, more preferably less than 1.25 m 2gxe2x88x921, still more preferably less than 0.9 m2gxe2x88x921, even still more preferably less than 0.5 m2gxe2x88x921. In each instance the indicated specific surface area refers the specific surface area prior to any compaction or compression that is performed during tabletting. In one embodiment the dibasic calcium phosphate dihydrate used in the invention has a specific surface area within the range of 0.2 and 1.5 m2gxe2x88x921, preferably between 0.3 m2gxe2x88x921 and 0.9 m2gxe2x88x921.
In a further embodiments of the invention the amount of DCPD is at least 50% (w/w) of the tablet, at least 60% (w/w) of the tablet and in the range of from 50% (w/w) to 70% (w/w) of the tablet. The excipient can further comprise at least 10% (w/w) mannitol. The detailed compositions of specific formulations that are suitable for the present invention can be found in Bavitz, J. F., and Shiromani, P. K., 1986, Drug Dev. Ind. Pharm. 12, 2481-92 and in Shiromani, P. K., and Bavitz, J. F., 1988, Drug Dev. Ind. Pharm. 14, 1375-87.
The reduced amount of lisinopril degradation product is believed to be due to the reduced specific surface area of the DCPD diluent. Accordingly, it will be appreciated that the invention is not restricted to the situation wherein substantially all of the DCPD is within a narrow (but large) size range, but also covers large and small particle size mixtures of DCPD that possess the desired specific surface area. Such mixtures could, for example be formed by combining milled and unmilled DCPD. The SSA limitation is a measure of the total surface area which can therefore accommodate mixtures.
In one particular embodiment the lisinopril used according to the invention is lisinopril dihydrate. However, other solid forms of lisinopril, such as other polymorphs, solvates or monohydrates are also contemplated. Thus, by the term xe2x80x98any formxe2x80x99 we include, solvated and desolvated forms, crystalline forms and amorphous forms.
The present invention relies on the use of grades of DCPD that are commonly used in direct compression techniques thus, individuals or companies interested in preparing lisinopril tablets which routinely practice direct compression/compaction or dry granulation techniques, will particularly benefit from the present invention.
The inventors have discovered that the 2.5 mg dosage tablets of lisinopril are susceptible to less DKP formation over time when DCPD with a lower specific surface area (SSA) than that conventionally used for wet granulation is used. It will be appreciated therefore, that because of the reduced propensity of the DCPD to dehydrate, there will be potential improvements in shelf-life of lisinopril tablets made with DCPD with a specific surface area less than 1.5 m2gxe2x88x921, particularly of low dosage tablets such as 5 mg or 2.5 mg.
According to a further aspect of the invention there is provided enhanced stability of 2.5 mg tablets of lisinopril comprising using or incorporating dibasic calcium phosphate dihydrate with a specific surface area of less than 1.5 m2gxe2x88x921. This can be effected by substituting unmilled DCPD for the conventionally used, milled DCPD.
The term stable as used herein, refers to the tendency to remain substantially in the same physical form for at least 6 months, more preferably at least a year, still more preferably at least 3 years, even still more preferably at least 5 years, when stored under ambient conditions (25xc2x0 C./60%RH) without external treatment.
The invention relies on the use of dibasic calcium phosphate with a specific surface area of less than 1.5 m2gxe2x88x921. Some manufacturers of dibasic calcium phosphate will be able to provide the desired SSA of the product on demand. Others sell specific grades of dibasic calcium phosphate (i.e. Rhodia Di-Tab(trademark) direct compression grade calcium phosphate dihydrate has a SSA of 0.77 m2gxe2x88x921; Landin et al., Int. J. Pharm. (1994) 107:247-249). The SSA of dibasic calcium phosphate dihydrate can be determined by the BET method using nitrogen adsorption in a Micromeritics Flowsorb II (Bunauer et al., (1938) J. Am. Chem. Soc., 60:309-319).
xe2x80x98Zestrilxe2x80x99 and xe2x80x98Zestoreticxe2x80x99 have received regulatory approval for use in the following indications:
Hypertension
xe2x80x98Zestrilxe2x80x99 is indicated in the treatment of essential hypertension and in renovascular hypertension. It may be used alone or concomitantly with other classes of antihypertensive agents.
xe2x80x98Zestoreticxe2x80x99 is indicated in the treatment of hypertension.
Congestive Heart Failure
xe2x80x98Zestrilxe2x80x99 is indicated in the management of congestive heart failure as an adjunctive treatment with diuretics and, where appropriate, digitalis. High doses reduce the risk of the combined outcomes of mortality and hospitalization.
Acute Myocardial Infarction
xe2x80x98Zestrilxe2x80x99 is indicated for the treatment of haemodynamically stable patients within 24 hours of an acute myocardial infarction, to prevent the subsequent development of left ventricular dysfunction or heart failure and to improve survival. Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin and beta-blockers.
Renal And Retinal Complications of Diabetes Mellitus
In normotensive insulin-dependent and hypertensive non-insulin-dependent diabetes mellitus patients who have incipient nephropathy characterised by microalbuminuria, xe2x80x98Zestrilxe2x80x99 reduces urinary albumin excretion rate. xe2x80x98Zestrilxe2x80x99 reduces the risk of progression of retinopathy in normotensive insulin-dependent diabetes mellitus patients.
According to the invention there is further provided a pharmaceutical composition comprising lisinopril, as active ingredient, in association with a pharmaceutically acceptable carrier, diluent or excipient and optionally other therapeutic ingredients, produced by a process comprising admixing lisinopril and DCPD with a specific surface area of less than 1.5 m2gxe2x88x921.
Compositions comprising other therapeutic ingredients are especially of interest in the treatment of hypertension, congestive heart failure, acute myocardial infarction and in renal and retinal complications of diabetes mellitus.
The invention also provides the use of lisinopril and dibasic calcium phosphate dihydrate with a specific surface area less than 1.5 m2gxe2x88x921 in the manufacture of a medicament for use in the treatment of a cardiovascular related condition, and in particular, a method of treating a hypertensive or congestive heart failure condition which method comprises administering to a subject suffering from said condition a therapeutically effective amount of a lisinopril composition produced by a process comprising admixing lisinopril and DCPD with a specific surface area of less than 1.5 m2gxe2x88x921.
The invention also provides a pharmaceutical composition comprising lisinopril produced by a process comprising admixing lisinopril and DCPD with a specific surface area of less than 1.5 m2gxe2x88x921, for use in treating hypertension, congestive heart failure, acute myocardial infarction and in renal and retinal complications of diabetes mellitus.
The invention also provides the use of a lisinopril composition produced by a process comprising admixing lisinopril and DCPD with a specific surface area of less than 1.5 m2gxe2x88x921 in treating hypertension, congestive heart failure, acute myocardial infarction and in renal and retinal complications of diabetes mellitus.
Any suitable route of administration may be employed for providing the patient with an effective dosage of drug comprising lisinopril according to the invention. For example, peroral or parenteral formulations and the like may be employed. Dosage forms include capsules, tablets, dispersions, suspensions and the like, e.g. enteric-coated capsules and/or tablets, capsules and/or tablets containing enteric-coated pellets of lisinopril. In all dosage forms lisinopril can be mixed with other suitable constituents. One route of administration is peroral using fast melt tablets.
The compositions of the invention comprise the compound of the invention. The compositions may be conveniently presented in unit dosage forms, and prepared by any methods known in the art of pharmacy.
In the practice of the invention, the most suitable route of administration as well as the magnitude of a therapeutic dose of a pharmaceutical composition comprising lisinopril according to the present invention, in any given case will depend on the nature and severity of the disease to be treated. The dose, and dose frequency, may also vary according to the age, body weight, and response of the individual patient.
In general, a suitable oral dosage form may cover a dose range from 0.5 mg to 150 mg total daily dose, administered in one single dose or equally divided doses. A preferred dosage range is from 1 mg to 60 mg.
Combination therapies comprising lisinopril according to the present invention and other active ingredients in separate dosage forms, or in one fixed dosage form, may also be used. Examples of such active ingredients include anti-bacterial compounds, non-steroidal anti-inflammatory agents, antacid agents, alginates, prokinetic agents, other antihypertensive agents, diuretics, digitalis, thrombolytics, aspirin and beta-blockers.